Treadmill Exercise Ameliorates Spatial Learning and Memory Deficits Through Improving the Clearance of Peripheral and Central Amyloid-Beta Levels

Aggregated amyloid beta (A beta) peptides are believed to play a decisive role in the pathology of Alzheimer's disease (AD). Previous evidence suggested that exercise contributes to the improvement of cognitive decline and slows down pathogenesis of AD; however, the exact mechanisms for this have not been fully understood. Here, we evaluated the effect of a 4-week moderate treadmill exercise on spatial memory via central and peripheral A beta clearance mechanisms following developed AD-like neuropathology induced by intra-hippocampal A beta(1-42) injection in male Wistar rats. We found A beta(1-42)-treated animals showed spatial learning and memory impairment which was accompanied by increased levels of amyloid plaque load and soluble A beta(1-42) (sA beta(1-42)), decreased mRNA and protein expression of neprilysin (NEP), insulin degrading enzyme (IDE) and low-density lipoprotein receptor-related protein-1 (LRP-1) in the hippocampus. A beta(1-42)-treated animals also exhibited a higher level of sA beta(1-42) and a lower level of soluble LRP-1 (sLRP-1) in plasma, as well as a decreased level of LRP-1 mRNA and protein content in the liver. However, exercise training improved the spatial learning and memory deficits, reduced both plaque load and sA beta(1-42) levels, and up-regulated expression of NEP, IDE, and LRP-1 in the hippocampus of A beta(1-42)-treated animals. A beta(1-42)-treated animals subjected to treadmill exercise also revealed decreased levels of sA beta(1-42) and increased levels of sLRP-1 in plasma, as well as increased levels of LRP-1 mRNA and protein in the liver. In conclusion, our findings suggest that exercise-induced improvement in both of central and peripheral A beta clearance are likely involved in ameliorating spatial learning and memory deficits in an animal model of AD. Future studies need to determine their relative contribution.